HETEROCYCLES

Short Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1597-1601
Received, 27th August, 2012, Accepted, 1st October, 2012, Published online, 16th October, 2012.
DOI: 10.3987/COM-12-S(N)111

■ BIOMIMETIC SYNTHESIS OF CHROBISIAMONE A FROM CASSIA sIAMEA

Yuichiro Tomizawa, Jun Deguchi, Tokio Ishikawa, Toshio Honda, and Hiroshi Morita*

Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Chrobisiamone A (1), an unique chromone dimer from leaves of Cassia siamea Lam. (Leguminosae), was synthesized from 5-acetonyl-7-hydroxy-2-methylchromone (2) in 4 steps through biomimetic Michael addition.

Chromones with a fused [6+6] system are a group of naturally occurring compounds widely distributed in nature. These structures represent molecules capable of binding to multiple receptors with high affinity and have a wide range of biological activities viz., tyrosine and protein kinase C inhibitors, anticancer, antifungal, antiviral, antitubulin, and antihypertensive agents.1 A khellin-based 7,7’-glycerol-bridged bischromone exhibits more effective anaphylactic activity than cromoglycate.2 Nebivolol, a 2,2’-bischroman tethered by 3-aza-1,5-pentanediol moiety, is an antihypertensive drug.3 In the investigation of the bioactive chromone-based compounds from tropical plants, we have isolated cassiarins A (3) and B with an unprecedented tricyclic skeleton from the leaves of C. siamea4, which showed a potent antiplasmodial activity. Cassiarin A (3) colud be derived from 5-acetonyl-7- hydroxy-2-methylchromone (2)5 based on a plausible biogenetic path.6

Further investigation of new bioactive compounds led to the isolation of a new dimeric chromone, chrobisiamone A (1) from the leaves of C. siamea.6 Chrobisiamone A (1) linked through their 2,2’-positions by methylene moiety. Few bischromone from natural resources has this type of ring system. Biogenetically, 1 might be derived from 5-acetonyl-7-hydroxy-2-methylchromone (2) by Michael addition of the chromone carbanion of C-2 methyl to C-2’ of a second chromone. Thereafter, some new dimeric alkaloids such as cassiarins D (4) and E have been isolated, which may be biosynthesized from 1.7 In this paper, we would like to describe the biomimetic synthesis of chrobisiamone A (1) via the known chromone, 5-acetonyl-7-hydroxy-2-methylchromone (2).

5-Acetonyl-7-hydroxy-2-methylchromone (2) was prepared by modified methods as described previously in 27% overall yield in 7 steps from 2,4,6-trihydroxylacetophenone.8 Two reactive moieties were protected before carrying out Michael addition. Ketalization with ethylene glycol and MOM protection of the hydroxyl group by Hegedus’ procedures gave a desired compound 6 (Scheme 1). One report about dimerization of chromone has published by Smith et al.9 In their attempts to remove the methyne proton from position 3 in 2,6-dimethylchromone, they found the treatment of 2,6-dimethylchromone by lithium di-isopropylamide (LDA) forming the chromone-chromanone skeleton by Michael addition. We carried out the same reaction condition for compound 6. Michael addition of compound 6 to the second molecule under LDA or LiHMDS failed to obtain a desired dimeric compound and only recovered starting material. In contrast to 2,6-dimethylchromone, a substituent at C-5 may have an influence on forming carbanion at C-14 by means of LDA. Ihara et al have succeeded to obtain a silyl enol ether of 3-methyl-2-cyclohexen-1-one by treatment of i-Pr2NEt and TBSOTf.10 In the same manner, compound 6 was treated with i-Pr2NEt and TBSOTf to afford an enol ether. Surprisingly, this attempt led directly to the formation of chromone-chromanone skeleton and gave 7 in 50% yield along with recovered starting material in 50% yield. Compound 7 was comparatively stable and did not decompose or convert into compound 6 by retro-Michael addition. Treatment of compound 7 with 2M HCl aqueous solution in MeOH gave chrobisiamone A (1) in 97% yield.

EXPERIMENTAL
General Experimental Procedures. Commercial reagents were used without purification. IR spectra were recorded on a JASCO FT/IR-4100 spectrophotometer. Highresolution ESIMS were obtained on a LTQ Orbitrap XL (Thermo Scientific). 1H and 13C NMR spectra were recorded on Bruker AV 400 spectrometers, and chemical shifts were referenced to the residual solvent peaks (δH 7.26 and δC 77.0 for chloroform-d and δH 3.31 and δC 49.0 for methanol-d4).

7-Hydroxy-2-methyl-5-[(2-methyl-1,3-dioxolan-2-yl)methyl]chromone (5) A solution of 5-acetonyl-7-hydroxy-2-methylchromone (2) (100 mg), ethylene glycol (60 µL), and p-TsOH•H2O (16 mg) in benzene (50 mL) was refluxed for 24 h in a Dean-Stark apparatus. The reaction mixture was cooled, poured into saturated aqueous NaHCO3 solution, the aqueous layer extracted with CHCl3, and washed with brine. The combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography on silica gel. Elution with hexane/EtOAc (1:1, v/v) gave ketal 3 (90 mg, 75%) as a colorless amorphous solid; IR (neat) 1560, 1616, 1647, 2883, 2932, 2980, 3101 cm-1; 1H NMR (400 MHz, CD3OD) δ 1.25 (3H, s), 2.33 (3H, d, J = 0.6 Hz), 3.78 (2H, m), 3.80 (2H, s), 3.86 (2H, m), 6.00 (1H, d, J = 0.6 Hz), 6.70 (1H, d, J = 2.4 Hz), 6.80 (1H, d, J = 2.4 Hz); HRESIMS m/z 277.1074 [calcd. for C15H17O5 (M+H)+, 277.1071].

7-(Methoxymethoxy)-5-[(2-methyl-1,3-dioxolan-2-yl)methyl]chromone (6) To a solution of 5 (90 mg) in CH2Cl2 (5 mL) were added successively i-Pr2NEt (68 µL) and MOMCl (37 µL) at 0 °C under Ar atmosphere. The resulting mixture was stirred at rt for 1.5 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution, the aqueous layer extracted with EtOAc, and washed with 1M HCl aqueous solution and brine. The combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography on silica gel. Elution with hexane/EtOAc (1:1, v/v) gave 6 (88 mg, 84%) as a colorless amorphous solid; IR (neat) 1610, 1657, 2885, 2931, 2959, 2982 cm-1; 1H NMR (400 MHz, CD3OD) δ 1.25 (3H, s), 2.35 (3H, d, J = 0.6 Hz), 3.48 (3H, s), 3.75 (2H, m), 3.83 (2H, s), 3.85 (2H, m), 5.29 (2H, s), 6.06 (1H, d, J = 0.6 Hz), 6.97 (1H, d, J = 2.5 Hz), 7.03 (1H, d, J = 2.5 Hz); HRESIMS m/z 321.1331 [calcd. for C17H21O6 (M+H)+, 321.1333].

7,7’-Bis(methoxymethoxy)-12,12’-bis(1,3-dioxolan-2-yl)-4’-(tert-butyldimethylsilyloxy)chrobisiamone A (7) To a solution of 6 (5 mg) in CH2Cl2 (2 mL) was added i-Pr2NEt (20 µL) and stirred for 30 min at 60 °C. After cooling to 0 °C TBSOTf (4 µL) was added dropwise and stirred for 30 min at the same temperature. The reaction mixture was poured into saturated aqueous NaHCO3 solution, the aqueous layer extracted with CHCl3, and washed with brine. The combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography on silica gel. Elution with hexane/EtOAc (2:1, v/v) gave 7 (2.9 mg, 50%) as a colorless amorphous solid; IR (neat) 1608, 1653, 2859, 2887, 2932, 2954 cm-1; 1H NMR (400 MHz, CD3OD) δ 0.15 (3H, s), 0.16 (3H s), 0.92 (9H, s), 1.22 (3H, s), 1.25 (3H, s), 2.95 (2H, s), 3.23 (1H, d, J = 13.3 Hz), 3.47 (3H, s), 3.48 (3H, s), 3.63 (1H, d, J = 13.3 Hz)3.77 (4H, m), 3.85 (4H, m), 4.94 (1H, s), 5.12 (2H, s), 5.30 (2H, s), 6.11 (1H,s), 6.51 (1H, d, J = 2.6 Hz), 6.55 (1H, d, J = 2.6 Hz), 6.99 (1H, d, J = 2.5 Hz), 7.02 (1H, d, J = 2.5 Hz); HRESIMS m/z 755.3465 [calcd. for C40H55O12Si (M+H)+, 755.3457].

Chrobisiamone A (1) A mixture of 7 (3 mg) and 2M HCl aqueous solution (10 drops) in MeOH (2 mL) was refluxed for 5 h. MeOH was removed and water was added. The mixture was extracted with CHCl3. The combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography on silica gel. Elution with hexane/EtOAc (1:3, v/v) gave 1 (1.8 mg, 97%) as a colorless amorphous solid; Spectroscopic data were corresponding to those of the article.6

ACKNOWLEDGMENTS
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from the Research Foundation for pharmaceutical Sciences and The Open Research Center Project.

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